The collection of plasma and cellular proteins comprising the complement system plays an important role in innate and acquired immunity to infections. Yet, unrestricted or misdirected complement activation can also contribute to human disease states. Oftentimes, such complement activation represents a key early event in disease development. The research supported by this grant over the years has investigated these aspects to understand the role of complement in renal disease. Complement factor H, decay accelerating factor, and complement receptor 1-related protein y (Crry) are responsible for limiting spontaneous, and immune complex- and antibody-mediated complement activation, while the receptors (R) for the C3a and C5a anaphylatoxins transduce many of the effects of this complement activation. As such, the work proposed here will investigate these five proteins and their roles in intrinsic renal endothelial and epithelial cells. In particular, complement-dependent mechanisms that lead to injury of intrinsic renal cells, infiltration of the kidney with extrinsic leukocytes, and ultimately, the development of chronic injury and irreversible organ failure will be examined. This work will be aided by the mouse model systems developed in the past funding period in which there are renal cellular injury and inflammation. Each is reflective of a particular human kidney disease. In addition, each requires a particular combination of abnormal or excessive functioning of C3aR, C5aR, factor H, decay accelerating factor, and Crry, emphasizing their relevancy. Through the use of genetically manipulated mice and recombinant proteins, and the techniques of bone marrow and kidney transplantation to determine effects of these proteins in specific cellular populations, relevant cellular pathways involved in disease pathophysiology will be dissected. Culture systems of these intrinsic renal cells will also be utilized to examine pathways and underlying cellular events that can be attributed to products of complement activation. These will be used in parallel with studies in the experimental animal, with the aim to recapitulate events occurring in vivo using these defined systems. Together, these can provide an unprecedented view of intrinsic events underlying disease pathogenesis that occur in the kidney from complement activation. The proposed work continues our efforts to understand how the complement system in involved in renal disease. Better and more specific therapy for these diseases in a clinical setting can come from this understanding of renal pathophysiology in animal models of human diseases. Kidney disease has become altogether too common in the United States, causing a great deal of illness, inconvenience, and even death. The goal of this work is to understand the root cause of human kidney diseases through the use of animal and cell culture model systems. The information from these studies will be used to determine treatment options for patients suffering from kidney diseases. [unreadable] [unreadable] [unreadable]